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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT04285567




Registration number
NCT04285567
Ethics application status
Date submitted
25/02/2020
Date registered
26/02/2020
Date last updated
12/11/2020

Titles & IDs
Public title
A Study to Compare the Efficacy and Safety of a Combined Regimen of Venetoclax and Obinutuzumab Versus Fludarabine, Cyclophosphamide, and Rituximab (FCR)/ Bendamustine And Rituximab (BR) in FIT Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without DEL (17P) or TP53 Mutation
Scientific title
A Prospective, Open-Label, Multicenter Randomized Phase III Study to Compare The Efficacy and Safety of A Combined Regimen of Venetoclax and Obinutuzumab Versus Fludarabine, Cyclophosphamide, and Rituximab (FCR)/Bendamustine and Rituximab (BR) in FIT Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without DEL(17P) or TP53 Mutation
Secondary ID [1] 0 0
2019-003327-37
Secondary ID [2] 0 0
CO41685
Universal Trial Number (UTN)
Trial acronym
CRISTALLO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphocytic Leukemia (CLL) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Obinutuzumab
Treatment: Drugs - Venetoclax
Treatment: Drugs - Fludarabine
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Rituximab
Treatment: Drugs - Bendamustine

Experimental: VEN + G - Participants will receive 12 cycles of treatment (each cycle is 28 days). Venetoclax (VEN) will be administered orally, daily, with a 5-week ramp-up period, starting on Cycle 1, Day 22 and administration will continue until the end of Cycle 12. Obinutuzumab (G) will be administered intravenously (IV) on Days 1 (and 2), 8, and 15 of Cycle 1 and on Day 1 of Cycles 2-6.

Active Comparator: FCR/BR - Participants will receive 6 cycles of Fludarabine + Cyclophosphamide + Rituximab (FCR) consisting of a single cycle of a single infusion of rituximab on Day 1 and fludarabine and cyclophosphamide infusions on Days 1-3 of each 28-day cycle or bendamustine (B) as infusions on Days 1 and 2 and a single cycle of rituximab on Day 1 of each 28-day cycle.


Treatment: Drugs: Obinutuzumab
Obinutuzumab 1000 mg will be administered IV on Days 1 (and 2), 8, and 15 of Cycle 1 and on Day 1 of Cycles 2-6.

Treatment: Drugs: Venetoclax
Venetoclax 20 mg will be administered orally, once daily starting on Day 22 of Cycle 1 for 7 days, then ramp up from 50 to 400 mg/day during Cycle 2 and continue at 400 mg/day from Day 1 of Cycle 3 till end of Cycle 12.

Treatment: Drugs: Fludarabine
Fludarabine will be administered in a dosage of 25 mg/m^2 IV on days 1, 2, and 3 of Cycles 1-6.

Treatment: Drugs: Cyclophosphamide
Cyclophosphamide will be administered in a dosage of 250 mg/m^2 IV on Days 1, 2, and 3 Cycles 1-6.

Treatment: Drugs: Rituximab
Rituximab will be administered at a dose of 375 mg/m^2 IV on Cycle 1, Day 1 followed by 500 mg/m^2 on Day 1 of Cycles 2-6.

Treatment: Drugs: Bendamustine
Bendamustine will be administered at a dose of 90 mg/m^2 IV on 2 consecutive days of Cycles 1-6.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Minimal Residual Disease (MRD) Response Rate in the First 140 Participants Recruited
Timepoint [1] 0 0
At Month 15
Secondary outcome [1] 0 0
Progression-free Survival (PFS)
Timepoint [1] 0 0
Every year after disease progression until end of study (up to 46 months)
Secondary outcome [2] 0 0
MRD Response Rate in Peripheral Blood (PB) at the End of Treatment Response Visit
Timepoint [2] 0 0
At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR
Secondary outcome [3] 0 0
MRD Response Rate in Bone Marrow (BM) at the End of Treatment Response Visit
Timepoint [3] 0 0
At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR
Secondary outcome [4] 0 0
Objective Response Rate (ORR)
Timepoint [4] 0 0
At Month 15
Secondary outcome [5] 0 0
Complete Response (CR) Rate
Timepoint [5] 0 0
At Month 15
Secondary outcome [6] 0 0
MRD Response Rate in PB of Participant With a CR/CR With Incomplete Blood Count (CRi) at Month 15
Timepoint [6] 0 0
At Month 15
Secondary outcome [7] 0 0
MRD Response Rate in the BM of Participants With a CR/CRi at the End of Treatment Visit
Timepoint [7] 0 0
At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR
Secondary outcome [8] 0 0
Duration of Objective Response (DOR)
Timepoint [8] 0 0
Every year after disease progression until end of study (up to 46 months)
Secondary outcome [9] 0 0
Best Overall Response
Timepoint [9] 0 0
Up to and including the assessment at Month 15
Secondary outcome [10] 0 0
Event-free Survival (EFS)
Timepoint [10] 0 0
Every year after disease progression until end of study (up to 46 months)
Secondary outcome [11] 0 0
Overall survival (OS)
Timepoint [11] 0 0
Every year after disease progression until end of study (up to 46 months)
Secondary outcome [12] 0 0
Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score - The MDASI-CLL is a questionnaire of 25 items related to CLL specific symptoms that a participant may have experienced in the past 24 hours. Participants were asked to rate the severity of 13 symptoms called mean core symptom severity (i.e., pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting, and numbness or tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fevers and chills, lymph node swelling, diarrhea, easy bruising or bleeding, and constipation) and 6 mean interference on life questions (i.e., general activity, walking, work, mood, relations with other people, and enjoyment of life) on a scale from 0 to 10 with 0 indicating that the symptom is "not present" or "did not interfere" with the participant's activities and 10 indicating "as bad as you can imagine" or "interfered completely".
Timepoint [12] 0 0
Arm VEN + G: Day 1 of Cycle 1-12, Day 28 after treatment completion/early termination (TC/ET), follow up (FU) visits; Arm FCR/BR: Day 1 of Cycle 1-6, Day 28 after TC/ET, end of combination treatment response visit and FU visit (up to 46 months)
Secondary outcome [13] 0 0
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQC-30) - The EORTC QLQ-C30 is a validated and reliable self-report measure consisting of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), and a global health status/global quality-of-life scale. The remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the additional symptoms experienced by patients with cancer and the perceived financial burden of treatment. The 28 function and symptom items were scored on a 4-point scale that ranged from "not at all" to "very much," and the 2 global health status/global quality-of-life items were scored on a 7-point scale that ranged from "very poor" to "excellent." Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).
Timepoint [13] 0 0
Arm VEN + G: Day 1 of Cycle 1-12, Day 28 after treatment completion/early termination (TC/ET), follow up (FU) visits; Arm FCR/BR: Day 1 of Cycle 1-6, Day 28 after TC/ET, end of combination treatment response visit and FU visit (up to 46 months)
Secondary outcome [14] 0 0
Number of Participants With Adverse Events (AEs)
Timepoint [14] 0 0
Up to 28 days after last dose of study drug or until initiation of another anti-cancer therapy (up to 46 months)

Eligibility
Key inclusion criteria
- Ability to comply with the study protocol, in the investigator's judgment

- Aged 18 years or older

- Have previously untreated documented Chronic Lymphocytic Leukemia (CLL) according to
the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria

- CLL requiring treatment according to the iwCLL criteria

- Cumulative Illness Rating Scale (CIRS) score = 6 and creatinine clearance (CrCl) = 70
mL/min

- Hematology values within the following limits, unless cytopenia is caused by the
underlying disease (i.e., no evidence of additional bone marrow (BM) dysfunction;
e.g., myelodysplastic syndrome, hypoplastic BM):

- Absolute neutrophil count = 1.0 x 109/L, unless there is BM involvement

- Platelet count = 75 x 109/L and more than 7 days since last transfusion, or = 30
x 109/L if there is BM involvement

- Adequate liver function as indicated by a total bilirubin, aspartate aminotransferase,
and Alanine transaminase = 2 times the institutional upper limit of normal (ULN)
value, unless directly attributable to the participant's CLL

- Life expectancy >6 months

- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraception and agreement to refrain from donating
eggs

- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive methods, and agreement to refrain from donating sperm
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Transformation of CLL to aggressive Non-Hodgkin's Lymphoma (NHL)

- Participants with Small Lymphocyclic Lymphoma (SLL)

- Known central nervous system involvement

- Participants with a history of confirmed progressive multifocal leukoencephalopathy
(PML)

- Detected del (17p) or TP53 mutation

- An individual organ/system impairment score of 4 as assessed by the Cumulative Illness
Rating Scale (CIRS) definition limiting the ability to receive the treatment regimen
of this trial with the exception of eyes, ears, nose, throat organ system

- Participants with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

- History of prior malignancy

- Participants with infections requiring IV treatment (Grade 3 or 4) within the last 8
weeks prior to enrollment

- Evidence of other clinically significant uncontrolled conditions including but not
limited to active or uncontrolled systemic infection (e.g., viral, bacterial, or
fungal)

- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
antibodies or known sensitivity or allergy to murine products

- Hypersensitivity to fludarabine, bendamustine, cyclophosphamide, rituximab,
obinutuzumab, or venetoclax or to any of the excipients (e.g., trehalose)

- Pregnant women and nursing mothers

- Vaccination with a live vaccine = 28 days prior to randomization

- Prisoners or participants who are institutionalized by regulatory or court order or
persons who are in dependence to the Sponsor or an investigator

- History of illicit drug or alcohol abuse within 12 months prior to screening, in the
investigator's judgment

- Positive test results for chronic hepatitis B virus (HBV) infection (defined as
positive hepatitis B surface antigen [HBsAg] serology)

- Positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology
testing)

- Participants with known infection with HIV or Human T-Cell Leukemia Virus 1 (HTLV-1)

- Any serious medical condition or abnormality in clinical laboratory tests that, in the
investigator's judgment, precludes the participant's safe participation in and
completion of the study

- Received any of the following agents within 28 days prior to the first dose of study
treatment:

- Immunotherapy

- Radiotherapy

- Hormone therapy

- Any therapies intended for the treatment of lymphoma/leukemia whether approved or
experimental

- Participants who have received the following agents:

- Strong and moderate CYP3A inhibitors/inducers within 7 days prior to the
initiation of study treatment

- Steroid therapy for anti-neoplastic intent with the exception of inhaled steroids
for asthma, topical steroids, or replacement/stress corticosteroids within 7 days
prior to the first dose of study drug administration

- Consumed grapefruit, grapefruit products, Seville oranges(including marmalade
containing Seville oranges), or star fruit within 3 days prior to the first dose
of study drug and throughout venetoclax administration

- Inability to swallow a large number of tablets.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,TAS,VIC
Recruitment hospital [1] 0 0
Canberra Hospital; Haematology Department - Canberra
Recruitment hospital [2] 0 0
Liverpool Hospital; Haematology - Liverpool
Recruitment hospital [3] 0 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [4] 0 0
Royal North Shore Hospital; Haematology Department - St. Leonards
Recruitment hospital [5] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 0 0
The Northern Hospital - Epping
Recruitment hospital [7] 0 0
Peter MacCallum Cancer Centre; Department of Haematology - Melbourne
Recruitment hospital [8] 0 0
Monash Medical Centre; Haematology - Melbourne
Recruitment postcode(s) [1] 0 0
2605 - Canberra
Recruitment postcode(s) [2] 0 0
2170 - Liverpool
Recruitment postcode(s) [3] 0 0
2444 - Port Macquarie
Recruitment postcode(s) [4] 0 0
2065 - St. Leonards
Recruitment postcode(s) [5] 0 0
7000 - Hobart
Recruitment postcode(s) [6] 0 0
VIC 3076 - Epping
Recruitment postcode(s) [7] 0 0
3002 - Melbourne
Recruitment postcode(s) [8] 0 0
3168 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
Maryland
Country [3] 0 0
United States of America
State/province [3] 0 0
Montana
Country [4] 0 0
United States of America
State/province [4] 0 0
New Jersey
Country [5] 0 0
United States of America
State/province [5] 0 0
New York
Country [6] 0 0
United States of America
State/province [6] 0 0
Oregon
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Tennessee
Country [9] 0 0
United States of America
State/province [9] 0 0
Texas
Country [10] 0 0
United States of America
State/province [10] 0 0
Utah
Country [11] 0 0
United States of America
State/province [11] 0 0
Virginia
Country [12] 0 0
France
State/province [12] 0 0
Caen
Country [13] 0 0
France
State/province [13] 0 0
Creteil
Country [14] 0 0
France
State/province [14] 0 0
Le Mans Cedex 02
Country [15] 0 0
France
State/province [15] 0 0
Lille
Country [16] 0 0
France
State/province [16] 0 0
Perpignan
Country [17] 0 0
France
State/province [17] 0 0
Pessac
Country [18] 0 0
France
State/province [18] 0 0
Pierre Benite
Country [19] 0 0
France
State/province [19] 0 0
Poitiers
Country [20] 0 0
France
State/province [20] 0 0
Reims
Country [21] 0 0
France
State/province [21] 0 0
Toulon
Country [22] 0 0
France
State/province [22] 0 0
Tours
Country [23] 0 0
Italy
State/province [23] 0 0
Emilia-Romagna
Country [24] 0 0
Italy
State/province [24] 0 0
Lazio
Country [25] 0 0
Italy
State/province [25] 0 0
Liguria
Country [26] 0 0
Italy
State/province [26] 0 0
Lombardia
Country [27] 0 0
Italy
State/province [27] 0 0
Piemonte
Country [28] 0 0
Italy
State/province [28] 0 0
Puglia
Country [29] 0 0
Italy
State/province [29] 0 0
Umbria
Country [30] 0 0
Spain
State/province [30] 0 0
Navarra
Country [31] 0 0
Spain
State/province [31] 0 0
Tenerife
Country [32] 0 0
Spain
State/province [32] 0 0
Barcelona
Country [33] 0 0
Spain
State/province [33] 0 0
Madrid
Country [34] 0 0
Spain
State/province [34] 0 0
Murcia
Country [35] 0 0
Spain
State/province [35] 0 0
Salamanca
Country [36] 0 0
Spain
State/province [36] 0 0
Sevilla
Country [37] 0 0
Spain
State/province [37] 0 0
Toledo

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This study will evaluate the efficacy and safety of venetoclax and obinutuzumab (VEN + G)
compared with fludarabine + cyclophosphamide + rituximab or bendamustine + rituximab (FCR/BR)
in FIT participants (FIT is defined by a cumulative illness rating scale [CIRS]/score of =6
and a normal creatinine clearance of =70 mL/min) with previously untreated CLL without
DEL(17P) or TP53 mutation requiring treatment. Eligible participants will be randomly
assigned in a 1:1 ratio to receive either VEN + G (Arm A) or FCR/BR (Arm B).
Trial website
https://clinicaltrials.gov/show/NCT04285567
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical trial
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Reference Study ID Number: CO41685 www.roche.com/about_roche/roche_worldwide.htm
Address 0 0
Country 0 0
Phone 0 0
888-662-6728 (U.S. Only)
Fax 0 0
Email 0 0
global-roche-genentech-trials@gene.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT04285567